HIV-1 not only attacks the immune system leading to systemic AIDS but also enters the brain where it indirectly injures neurons and produces a constellation of symptoms known collectively as neuro- AIDS. Substantial evidence suggests that opiates may exacerbate the severity of HIV-1 disease and accelerate its progression to AIDS. In contrast, other studies have suggested that opiate exposure may have a protective effect and actually reduce the severity of disease and slow its progression to AIDS. Despite the importance of better understanding the linkages between drug abuse and the development of AIDS as well as AIDS-related neurological disease, there have been few studies of these relationships in animal models. To date, only two published studies have taken advantage of the simian immunodeficiency virus (SIV) infected macaque model, even though this model best reproduces the immunological, virological and neurological features of human HIV-disease. Over the past several years, we have focused our efforts on developing macaque models of neuro- AIDS. We recently completed studies on a cohort of nine rhesus macaques infected with neurovirulent strains of SIVmac. All monkeys in this cohort showed behavioral and neurophysiological impairments when tested on a battery that included reaction time, working memory and motor skill tasks as well as sensory and motor evoked potentials. Neuropathological and stereological studies in the same monkeys demonstrated microglial nodules and multinucleate giant cells, the hallmarks of HIV brain infection, as well as significant neuronal cell loss. Recently, several pathogenic strains of chimeric simian-human immunodeficiency virus have been developed that contain the tat, rev, vpu, and env of HIV-1 in a genetic background of SIVmac239. One of these viruses, SHIVKU-2MC4, causes rapid CD4+ T cell depletion and neuro-AIDS following inoculation into rhesus macaques. This virus represents a significant advance as an animal model because the Env of HIV-1 has been implicated in HIV-1-induced neuropathogenesis and because the Env proteins of SIV and HIV-1 are only distantly related. In this application, we propose four specific aims that focus on the behavioral, neurological, immunological and virological consequences of opiate-dependence in SHIV-infected rhesus macaques. A fifth specific aim will investigate the cellular and molecular mechanisms by which morphine influences viral replication and co-receptor expression in lymphocyte and macrophage populations.